Changes in cellular biochemical pathways are fundamental to herpesvirus persistence and oncogenicity. We will employ new global approaches to identify viral genes that modulate cellular pathways and to identify the pathways that are altered, and then we will elucidate the mode of action of these altered pathways within the infected cell. Our approach will be comparative. The program will include the study of viruses in each of the three families of herpesviruses: alpha, herpes simplex type 1 virus and pseudorabies virus; beta, human cytomegalovirus; and gamma, Epstein- Barr virus and Kaposi sarcoma-associated herpes virus. Some herpes viruses contribute to human cancers (Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus), while others are not known to do so. Consequently, our program will compare tumor viruses with closely related non-tumor viruses. The long-term objective of the program is to better understand the mechanisms by which herpesviruses persist and contribute to oncogenesis in the infected host. We will search for additional viral genes that mediate persistence and oncogenicity, and we will study the mechanism of action of new genes that are identified. We also will identify cellular genes whose level of expression change after infection, and test the hypothesis that some of these altered cellular genes influence the outcome of the virus-host interaction, contributing to the persistence and/or oncogenicity of the viruses. The individual research projects are as follows. Project 1, Roizman. Comparative role of cellular functions in herpes simplex type 1 virus infection. Project 2, Enquist Comparative alpha-herpesvirus (herpes simplex type 1 virus and pseudorabies virus) infection of the nervous system. Project 3, Shenk: Viral and cell gene function in human cytomegalovirus replication and latency. Project 4, Moore: Viral and cellular gene regulation in Kaposi sarcoma-associated herpesvirus-associated tumors. Project 5, Kieff: Epstein-Barr virus and cell gene expression in latency and oncogenesis.